1. Field of the Invention
The present invention relates to vinca alkaloid N-oxides having activity for treating hyperproliferative disorders. Further, the invention relates to pharmaceutical compositions and methods of using vinca alkaloid N-oxides, alone or in combination with one or more other active agents or treatments, to treat hyperproliferative disorders.
2. Related Art
One in every four deaths in the United States is due to cancer, and cancer is the second leading cause of death. U.S. Cancer Statistics Working Group; United States Cancer Statistics: 2000 Incidence, Atlanta (GA): Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute (2003). The National Cancer Institute reports that almost 10 million Americans have a history of invasive cancer, while the American Cancer Society estimates that in the year 2004, over 1.3 million Americans will receive a diagnosis of invasive cancer with over a half million cases resulting in death. American Cancer. Society, Cancer Facts & Figures 2004. These statistics exclude the 1 million cases of basal and squamous cell skin cancers that are expected to be diagnosed in the United States.
Cancers are classified based on the organ and cell tissue from which the cancer originates, including: (i) carcinomas (most common kind of cancer which originates in epithelial tissues, the layers of cells covering the body's surface or lining internal organs and various glands); (ii) leukemias (origination in the blood-forming tissues, including bone marrow, lymph nodes and the spleen); (iii) lymphomas (originates in the cells of the lymph system); (iv) melanomas (originates in the pigment cells located among the epithelial cells of the skin); and (v) sarcomas (originates in the connective tissues of the body, such as bones, muscles and blood vessels). (See Molecular Biology of the Cell: Third Edition, “Cancer,” Chapter 24, pp. 1255-1294, B. Alberts et al., (eds.), Garland Publishing, Inc., New York (1994); and Stedman's Pocket Medical Dictionary; Williams and Wilkins, Baltimore (1987)). Within these broad cancer classifications, there are over one hundred cancer subclassifications, such as breast, lung, pancreatic, colon, and prostate cancer, to name a few.
Cancer cells develop as a result of damage to a cell's DNA (i.e., altered DNA sequence or altered expression pattern) from exposure to various chemical agents, radiation, viruses, or when some not-yet-fully-understood internal, cellular signaling event occurs. Most of the time when a cell's DNA becomes damaged, the cell either dies or is able to repair the DNA. However, for cancer cells, the damaged DNA is not repaired and the cell continues to divide, exhibiting modified cell physiology and function.
Neoplasms, or tumors, are masses of cells that result from an aberrant, accelerated rate of growth (i.e., hyperproliferative cell growth). As long as the tumor cells remain confined to a single mass, the tumor is considered to be benign. However, a cancerous tumor has the ability to invade other tissues and is termed malignant. In general, cancer cells are defined by two heritable properties: the cells and their progeny 1) reproduce in defiance of normal restraints, and 2) invade and colonize the territories of other cells.
Cancerous tumors are comprised of a highly complex vasculature and differentiated tissue. A large majority of cancerous tumors have hypoxic components, which are relatively resistant to standard anti-cancer treatment, including radiotherapy and chemotherapy. Brown, Cancer Res. 59:5863 (1999); and Kunz, M. et al., Mol. Cancer. 2:1 (2003). Thomlinson and Gray presented the first anatomical model of a human tumor that describes a 100 to 150 μm thick hypoxic layer of tissue located between the blood vessels and necrotic tumor tissues.
Research has shown that the hypoxic tissues within a number of cancerous tumors promote the progression of the cancer by an array of complex mechanisms. See, Brown, supra, and Kunz et al., supra. Among these are activation of certain signal transduction pathways and gene regulatory mechanisms, induction of selection processes for gene mutations, tumor cell apoptosis and tumor angiogenesis. Most of these mechanisms contribute to tumor progression. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. Therapies that target hypoxic tissues within a tumor would certainly provide improved treatments to patients suffering from tumor-related cancers and/or disorders.
In addition to cancer, there exist a number of hyperproliferative diseases and/or disorders that are associated with the onset of hypoxia in a given tissue. For example, Shweiki et al. explains that inadequate oxygen levels often lead to neovascularization in order to compensate for the needs of the hypoxic tissue. Neovascularization is mediated by expression of certain growth factors, such as vascular endothelial growth factor (VEGF). Shweiki et al., Nature 359:843 (1992). However, when certain tissues or growth factors are either directly or indirectly upregulated in response to hypoxia without sufficient feedback mechanisms for controlling tissue expression, various diseases and/or disorders may ensue (i.e., by hypoxia-aggravated hyperproliferation). By way of example, hypoxia-aggravated hyperproliferative diseases and/or disorders having over-expressed levels of VEGF include ocular angiogenic diseases, such as age-related macular degeneration and diabetic retinopathy, as well as cirrhosis of the liver. See Frank, Ophthalmic Res. 29:341 (1997); Ishibashi et al., Graefe's Archive Clin. Exp. Ophthamol. 235:159 (1997); Corpechot et al., Hepatology 35:1010 (2002).
Vinca alkaloids are a class of chemotherapeutic agents originally discovered in the Madagascar periwinkle. Currently known vinca alkaloids include vinblastine, vincristine, vindesine and vinorelbine. Vinca alkaloids act by inhibiting mitosis in metaphase. These alkaloids bind to tubulin, thus preventing the cell from making the spindles it needs to be able to move its chromosomes around as it divides. These alkaloids also seem to interfere with cells' ability to synthesize DNA and RNA. They are all administered intravenously in their sulfate form once a week; these solutions are fatal if they are administered incorrectly, and can cause considerable tissue irritation if they leak out of the vein. See U.S. Pat. No. 6,555,547 for further detail.
U.S. Pat. No. 6,365,735 discloses a process for preparing vinca alkaloids of the general formula (I):

in which:
R′1 represents a hydrogen atom or an alkoxy, acyl, formyl or halogenoacyl group,
R′2 represents a hydrogen atom or an alkyl group,
R′3 and R″3 are identical or different and each independently represents a hydrogen atom or a hydroxyl or alkanoyloxyl group, or else R′3 and R″3 together form a carbonyl group or else R′3 and R′5 together form an epoxy bridge or a double bond,
R′4 represents a hydrogen atom or an alkyloxycarbonyl, hydroxymethyl or alkanoyloxymethyl group, preferably an alkyloxycarbonyl group,
R′5 and R″5 are identical or different and each independently represents a hydrogen atom or a hydroxyl, alkanoyloxyl, ethyl or 2-hydroxyethyl group,
R′6 represents a hydrogen atom or an ethyl, 2-hydroxyethyl or acetyl group,
R′7 represents a hydrogen atom or a cyanide group,
R1 represents a hydrogen atom or an alkyl, formyl or acyl group, preferably hydrogen or an alkyl group,
R2 represents a hydrogen atom or an alkoxy group,
R3 represents a hydrogen atom or a hydroxyl or alkanoyloxyl group, or else R3 and R4 together form an epoxy bridge or a double bond,
R4 represents a hydrogen atom or a hydroxyl or alkanoyloxyl group, or else R4 and R5 together form an epoxy bridge,
R6 represents an alkyloxycarbonyl, hydrazido, acetamido, hydroxymethyl or alkanoyloxymethyl group,
R5 and R7 represent a hydrogen atom or a hydroxyl or alkanoyloxyl group, as well as their addition salts with acids and their quaternary ammonium salts.
Disclosed also are additional classes of vinca alkaloids as well specific vinca alkaloids such as vinblastine, vincristine, anhydrovinblastine and vinorelbine.